Type I or insulin dependent diabetes mellitus (IDDM) is a major health problem. Severe insulin deficiency is the hallmark of the disease process. The transplantation of isolated pancreatic islets is an experimental procedure with the objective of providing the IDDM with an endogenous source of insulin. Evidence is accumulating that clinical islet transplantation of human islets. Thus other approaches, such as the preparation of islets from a closely related animal species, such as the monkey, will have to be explored as an alternative source of donor tissue. The BB/W rat is an important animal model of type 1 diabetes which has many features in common with the clinical syndrome, such as insulitis, ketoacidosis, and severe hyperglycemia associates with B-cell destruction. Our earlier studies on the transplantation of islets into the spontaneously diabetic BB/W rat have shown that: 1) Indefinite islet allograft survival can be achieved without sustained immunosuppression provided that the islets are injected into the immunologically privileged abdominal testis. 2) Insulin determination as a tool for detecting viable B-cells indicate excellent preservation of islets transplanted into the testis. 3) Studies on the mechanisms of testicular immune privilege suggest that neither testosterone nor progesterone is the factor responsible for the remarkable survival of abdominal intratesticular, islet allografts. 4) Extended survival of intratesticular islet xenografts is possible in the BB/W rat with cyclosporine. We propose now as our first aim to examine whither long-term islet allograft survival, after immunosuppression is stopped, depends on the induction of tolerance in the host to islet antigen. As a second aim we will continue to explore factors such as inhibin, produced by the Sertoli cell, that might mediate testicular immune privilege. As the third aim the effect of intratesticular islet allografts on alpha cell function of both the endogenous pancreas and of the graft will be examined. As the fourth aim we plan to apply the transplantation model towards the grafting of concordant xenografts into a higher animal such as the monkey. These studies might provide new insight into the phenomenon of transplantation tolerance, and might have practical implications for clinical islet xenotransplantation.